Abstract 5510: TAS102 synergizes with regorafenib against colorectal and gastric cancer cells
Authors: Jun Zhang, Lanlan Zhou, Shuai Zhao, Wafik S. El-Deiry
Journal: Cancer Research (2023)

Abstract TAS-102 is an oral formulation consisting of trifluridine (FTD) and thymidine phosphorylase inhibitor tipiracil hydrochloride (TPI). Regorafenib is a multi-targeted tyrosine kinase inhibitor, it inhibits the activities of VEGFR2 and 3, Ret, Kit, PDGFR and Raf kinases and results in the inhibition of tumor angiogenesis and cell proliferation. TAS102 or regorafenib monotherapy can lead to an overall survival benefit in metastatic colorectal cancer (mCRC) patient previously treated with conventional chemotherapy and target therapy (Arnold et al., 2018). TAS102 in combination with bevacizumab, a monoclonal antibody against vascular endothelial growth factor A (VEGF-A), is associated with a significant and clinically relevant improvement in progression-free survival in colorectal cancer (C-TASK FORCE)(Kuboki et al., 2017; Pfeiffer et al., 2020). FTD can synergize with nintedanib to inhibit the growth of colorectal cancer xenografts(Suzuki, Nakagawa, Matsuoka, &amp; Takechi, 2016). We previously reported that regorafenib combined with a fluoropyrimidine can delay disease progression in case reports of multidrug-resistant mCRC patients(Marks et al., 2015). Therefore, we hypothesized that the combination of TAS102 and regorafenib may be active in CRC and other gastrointestinal (GI) cancers, and may in the future provide a treatment option for patients with advanced GI cancer. We investigated the therapeutic effect of TAS102 in combination with regorafenib in preclinical studies employing cell culture, colonosphere assays that enrich for cancer stem cells, and in vivo. We found that TAS102 in combination with regorafenib has synergistic activity against multiple GI cancers in vitro including colorectal and gastric cancer, but not liver cancer cells. TAS102 inhibits colonosphere formation and this effect is potentiated by regorafenib. In vivo anti-tumor effects of TAS102 plus regorafenib appear to be due to anti-proliferative effects, necrosis and angiogenesis inhibition. Growth inhibition by TAS102 plus regorafenib occurs in xenografted tumors regardless of p53, KRAS or BRAF mutations, although more potent tumor suppression was observed with wild-type p53. Regorafenib significantly inhibits TAS102-induced angiogenesis and microvessel density in xenografted tumors, and inhibits TAS102-induced ERK1/2 activation regardless of RAS or BRAF status in vivo. Collectively, TAS102 plus regorafenib is a synergistic drug combination in preclinical models of GI cancer, with regorafenib suppressing TAS102-induced increase in microvessel density and p-ERK as contributing mechanisms. The drug combination may be further tested in gastric and other GI cancers. Citation Format: Jun Zhang, Lanlan Zhou, Shuai Zhao, Wafik S. El-Deiry. TAS102 synergizes with regorafenib against colorectal and gastric cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5510.